Paclitaxel and Erlotinib-co-loaded Solid Lipid Core Nanocapsules: Assessment of Physicochemical Characteristics and Cytotoxicity in Non-small Cell Lung Cancer

  • Biki Gupta
  • Bijay Kumar Poudel
  • Shobha Regmi
  • Shiva Pathak
  • Hima Bindu Ruttala
  • Milan Gautam
  • Gyeong Jin An
  • Jee-Heon Jeong
  • Han-Gon Choi
  • Chul Soon YongEmail author
  • Jong Oh KimEmail author
Research Paper



Lung cancer is the leading cause of cancer-related deaths. The aim of this study was to design solid lipid core nanocapsules (SLCN) comprising a solid lipid core and a PEGylated polymeric corona for paclitaxel (PTX) and erlotinib (ERL) co-delivery to non-small cell lung cancer (NSCLC), and evaluate their physicochemical characteristics and in vitro activity in NCI-H23 cells.


PTX/ERL-SLCN were prepared by nanoprecipitation and sonication and physicochemically characterized by dynamic light scattering, transmission electron microscopy, differential scanning calorimetry, X-ray diffraction, and Fourier-transform infrared spectroscopy. In vitro release profiles at pH 7.4 and pH 5.0 were studied and analyzed. In vitro cytotoxicity and cellular uptake and apoptosis assays were performed in NCI-H23 cells.


PTX/ERL-SLCN exhibited appropriately-sized spherical particles with a high payload. Both PTX and ERL showed pH-dependent and sustained release in vitro profiles. PTX/ERL-SLCN demonstrated concentration- and time-dependent uptake by NCI-H23 cells and caused dose-dependent cytotoxicity in the cells, which was remarkably greater than that of not only the free individual drugs but also the free drug cocktail. Moreover, well-defined early and late apoptosis were observed with clearly visible signs of apoptotic nuclei.


PTX/ERL-SLCN could be employed as an optimal approach for combination chemotherapy of NSCLC.

Key Words

Erlotinib paclitaxel solid lipid core nanocapsules non-small cell lung cancer 



Acetate buffer solution


Didodecyldimethylammonium bromide


Dynamic light scattering


Dulbecco’s Modified Eagle’s medium


Dimethyl sulfoxide


Differential scanning calorimetry


Epidermal growth factor receptor




Fluorescence-activated cell sorting


Fetal bovine serum


Fourier-transform infrared spectroscopy


Glyceryl monostearate


High-performance liquid chromatography


Loading capacity


Loading efficiency


3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide


Molecular weight cut-off


Non-small cell lung cancer


Phosphate-buffered saline


Polydispersity index


Poly(ethylene glycol)




Small cell lung cancer


Soya lecithin


Solid lipid core nanocapsules


Transmission electron microscopy


Tyrosine kinase inhibitor


X-ray diffraction


Acknowledgments and Disclosures

This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2015R1A2A2A01004118, 2015R1A2A2A04004806, and by the Medical Research Center Program (2015R1A5A2009124) through the NRF funded by MSIP).

Compliance with Ethical Standards

Conflict of Interest

The authors have no conflict of interest to declare.

Supplementary material

11095_2017_2337_MOESM1_ESM.docx (1.2 mb)
ESM 1 (DOCX 1178 kb)


  1. 1.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. Ca-Cancer J Clin. 2015;65:87–108.CrossRefPubMedGoogle Scholar
  2. 2.
    Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008;83(5):584–94.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Zarogoulidis K, Zarogoulidis P, Darwiche K, Boutsikou E, Machairiotis N, Tsakiridis K, et al. Treatment of non-small cell lung cancer (NSCLC). J Thorac Dis. 2013;5(S4):S389–96.Google Scholar
  4. 4.
    Cosaert J, Quoix E. Platinum drugs in the treatment of non-small cell lung cancer. Br J Cancer. 2002;87(8):825–33.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Langer CJ, Manola J, Bernardo P, Kugler JW, Bonomi P, Cella D, et al. Cisplatin-based therapy for elderly patients with advanced non-small-cell lung cancer: implications of eastern cooperative oncology group 5592, a randomized trial. J Natl Cancer Inst. 2002;94(3):173–81.Google Scholar
  6. 6.
    Rosell R, Crino L. Pemetrexed combination therapy in the treatment of non-small cell lung cancer. Semin Oncol. 2002;29:23–9.Google Scholar
  7. 7.
    Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczesna A, Juhasz E, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicenter, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2010;11(6):521–9.Google Scholar
  8. 8.
    Sandler A, Ettinger DS. Gemcitabine: single-agent and combination therapy in non-small cell lung cancer. Oncologist. 1999;4(3):241–51.PubMedGoogle Scholar
  9. 9.
    Chen YM, Perng RP, Lee YC, Shih JF, Lee CS, Tsai CM, et al. Paclitaxel plus carboplatin, compared with paclitaxel plus gemcitabine, shows similar efficacy while more cost-effective: a randomized phase II study of combination chemotherapy against inoperable non-small cell lung cancer previously untreated. Ann Oncol. 2002;13(1):108–15.Google Scholar
  10. 10.
    Freco FA. Paclitaxel-based combination chemotherapy in advanced non-small cell lung cancer. Lung Cancer. 2001;34:S53–6.CrossRefGoogle Scholar
  11. 11.
    Ramalingam S. First-line chemotherapy for advanced-stage non-small-cell lung cancer: focus on docetaxel. Clin Lung Cancer. 2005;7(Suppl 3):S77–82.CrossRefPubMedGoogle Scholar
  12. 12.
    Yang XQ, Li CY, MF X, Zhao H, Wang D. Comparison of first-line chemotherapy based on irinotecan or other drugs to treat non-small cell lung cancer in stage IIIB/IV: a systematic review and meta-analysis. BMC Cancer. 2015;15:949.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Grunberg SM, Crowley JJ, Livingston RB, Muggia FM, MacDonald JS, Williamson SK, et al. Treatment of non-small-cell lung cancer with vinblastine and very high-dose cisplatin. A southwest oncology group study. Cancer Chemother Pharmacol. 1991;28(3):211–3.Google Scholar
  14. 14.
    Faller BA, Pandit TN. Safety and efficacy of vinorelbine in the treatment of non-small cell lung cancer. Clin Med Insights Oncol. 2011;5:131–44.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Monnet I, de Cremoux H, Soulie P, Saltiel-Voisin S, Bekradda M, Saltiel JC, et al. Oxaliplatin plus vinorelbine in advanced non-small-cell lung cancer: final results of a multicenter phase II study. Ann Oncol. 2002;13:103–7.Google Scholar
  16. 16.
    Ardizzoni A, Antonelli G, Grossi F, Tixi L, Cafferata M, Rosso R. The combination of etoposide and cisplatin in non-small-cell lung cancer (NSCLC). Ann Oncol. 1999;10(suppl 5):S13–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Sculier JP, Ghisdal L, Berghmans T, Branle F, Lafitte JJ, Vallot F, et al. The role of mitomycin in the treatment of non-small cell lung cancer: a systematic review with meta-analysis of the literature. Br J Cancer. 2001;84(9):1150–5.Google Scholar
  18. 18.
    Hesketh PJ, Tansan S, Caquioa PB, Hesketh A, Blanchard R, DiMartino N, et al. Treatment of advanced non-small cell lung cancer with very high-dose cisplatin combined with etoposide and mitomycin C. Cancer. 1993;71(3):717–20.Google Scholar
  19. 19.
    Cullen MH, Billingham LJ, Woodroffe CM, Chetiyawardana AD, Gower NH, Joshi R, et al. Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life. J Clin Oncol. 1999;17(10):3188–94.Google Scholar
  20. 20.
    Babiak A, Hetzel J, Godde F, Konig HH, Pietsch M, Hetzel M, et al. Vinorelbine for second-line chemotherapy in NSCLC – a phase II trial. Br J Cancer. 2007;96:1052–6.Google Scholar
  21. 21.
    Choi JY, Thapa RK, Yong CS, Kim JO. Nanoparticle-based combination drug delivery systems for synergistic cancer treatment. J Pharm Invest. 2016;46(4):325–39.CrossRefGoogle Scholar
  22. 22.
    Lilenbaum RC, Herndon JE, List MA, Desch C, Watson DM, Miller AA, et al. Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: the cancer and leukemia group B (study 9730). J Clin Oncol. 2005;23(1):190–6.Google Scholar
  23. 23.
    Chen YM, Shih JF, Lee CS, Chen MC, Lin WC, Tsai CM, et al. Study of docetaxel and ifosfamide combination chemotherapy in non-small-cell lung cancer patients failing previous chemotherapy with or without paclitaxel. Lung Cancer. 2003;39(2):209–14.Google Scholar
  24. 24.
    Sekine I, Saijo N. Novel combination chemotherapy in the treatment of non-small cell lung cancer. Expert Opin Pharmacother. 2000;1(6):1131–61.CrossRefPubMedGoogle Scholar
  25. 25.
    Tran TH, Thapa RK, Nguyen HT, Pham TT, Ramasamy T, Kim DS, et al. Combined phototherapy in anti-cancer treatment: therapeutics design and perspectives. J Pharm Invest. 2016;46(6):505–17.Google Scholar
  26. 26.
    Lilenbaum R, Villaflor VM, Langer C, O’Byrne K, O’Brien M, Ross HJ, et al. Single-agent versus combination chemotherapy in patients with advances non-small cell lung cancer and a performance status of 2: prognostic factors and treatment selection based on two large randomized clinical trials. J Thorac Oncol. 2009;4(7):869–74.Google Scholar
  27. 27.
    Santos FN, de Castria TB, Cruz MRS, Riera R. Chemotherapy for advances non-small cell lung cancer in the elderly population. (review) Cochrane Database Syst Rev. 2015;
  28. 28.
    Ramalingam S, Belani CP. Paclitaxel for non-small cell lung cancer. Expert Opin Pharmacother. 2004;5(8):1771–80.CrossRefPubMedGoogle Scholar
  29. 29.
    Chu Q, Vincent M, Logan D, Mackay JA, Evans WK. Taxanes as first-line therapy for advanced non-small cell lung cancer: a systematic review and practice guideline. Lung Cancer. 2005;50:355–74.CrossRefPubMedGoogle Scholar
  30. 30.
    Grindelli C, Bareschino MA, Schettino C, Rossi A, Maione P, Ciardiello F. Erlotinib in non-small cell lung cancer treatment: current status and future development. Oncologist. 2007;12:840–9.CrossRefGoogle Scholar
  31. 31.
    JL X, Jin B, Ren ZH, Lou YQ, Zhou ZR, Yang QZ, et al. Chemotherapy plus erlotinib versus chemotherapy alone for treating advanced non-small cell lung cancer: a meta-analysis. PLoS One. 2015;
  32. 32.
    Leung L, Mok TSK, Loong H. Combining chemotherapy with epidermal growth factor receptor inhibition in advanced non-small cell lung cancer. Ther Adv Med Oncol. 2012;4(4):173–81.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Ma L, Kohli M, Smith A. Nanoparticles for combination drug therapy. ACS Nano. 2013;7(11):9518–25.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Hu CMJ, Aryal S, Zhang L. Nanoparticle-assisted combination therapies for effective cancer treatment. Ther Del. 2010;1(2):323–34.CrossRefGoogle Scholar
  35. 35.
    Gupta B, Yong CS, Kim JO. Solid matrix-based lipid nanoplatforms as carriers for combinational therapeutics in cancer. J Pharm Invest. 2017;47(6):461–73.CrossRefGoogle Scholar
  36. 36.
    Sharma A, Sharma US. Liposomes in drug delivery: progress and limitations. Int J Pharm. 1997;154:123–40.CrossRefGoogle Scholar
  37. 37.
    Sercombe L, Veerati T, Moheimani F, SY W, Sood AK, Hua S. Advances and challenges of liposome assisted drug delivery. Front Pharmacol. 2015;6:Article 286.CrossRefPubMedGoogle Scholar
  38. 38.
    Puri A, Loomis K, Smith B, Lee JH, Yavlovich A, Heldman E, et al. Lipid-based nanoparticles as pharmaceutical drug carriers: from concepts to clinic. Crit Rev Ther Drug Carrier Syst. 2009;26(6):523–80.Google Scholar
  39. 39.
    Krishnamurthy S, Vaiyapuri R, Zhang L, Chan JM. Lipid-coated polymeric nanoparticles for cancer drug delivery. Biomater Sci. 2015;3:923–36.CrossRefPubMedGoogle Scholar
  40. 40.
    Gupta B, Poudel BK, Pathak S, Tak JW, Lee HH, Jeong JH, et al. Effects of formulation variables on the particle size and drug encapsulation of imatinib-loaded solid lipid nanoparticles. AAPS PharmSciTech. 2016;17(3):652–62.Google Scholar
  41. 41.
    Varshosaz J, Ghaffari S, Khoshayand MR, Atyabi F, Azarmi S, Kobarfard F. Development and optimization of solid lipid nanoparticles of amikacin by central composite design. J Liposome Res. 2010;20(2):97–104.CrossRefPubMedGoogle Scholar
  42. 42.
    Emami J, Mohiti H, Hamishehkar H, Varshosaz J. Formulation and optimization of solid lipid nanoparticle formulation for pulmonary delivery of budesonide using Taguchi and box-Behnken design. Res Pharm Sci. 2015;10(1):17–33.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Hao J, Fang X, Zhou Y, Wang J, Guo F, Li F, et al. Development and optimization of solid lipid nanoparticle formulation for ophthalmic delivery of chloramphenicol using a box-Behnken design. Int J Nanomedicine. 2011;6:683–92.Google Scholar
  44. 44.
    Gupta B, Pathak S, Poudel BK, Regmi S, Ruttala HB, Gautam M, et al. Folate receptor-targeted hybrid lipid-core nanocapsules for sequential delivery of doxorubicin and tanespimycin. Colloids Surf B: Biointerfaces. 2017;155:83–92.Google Scholar
  45. 45.
    Kobayashi H, Watanabe R, Choyke PL. Improving conventional enhanced permeability and retention (EPR) effects; what is the appropriate target? Theranostics. 2014;4(1):81–9.CrossRefGoogle Scholar
  46. 46.
    Gupta B, Poudel BK, Tran TH, Pradhan R, Cho HJ, Jeong JH, et al. Modulation of pharmacokinetic and cytotoxicity profile of imatinib base by employing optimized nanostructured lipid carriers. Pharm Res. 2015;32(9):2912–27.Google Scholar
  47. 47.
    Gupta B, Ramasamy T, Poudel BK, Pathak S, Regmi S, Choi JY, et al. Development of bioactive PEGylated nanostructured platforms for sequential delivery of doxorubicin and imatinib to overcome drug resistance in metastatic tumors. ACS Appl Mater Interfaces. 2017;9:9280–90.Google Scholar
  48. 48.
    Korsmeyer RW, Gurny R, Doelker E, Buri P, Peppas NA. Mechanisms of solute release from porous hydrophilic polymers. Int J Pharm. 1983;15:25–35.CrossRefGoogle Scholar
  49. 49.
    Rejman J, Oberle V, Zuhorn IS, Hoekstra D. Size-dependent internalization of particles via the pathways of clathrin- and caveolae-mediated endocytosis. Biochem J. 2004;377(1):159–69.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.College of PharmacyYeungnam UniversityGyeongsanSouth Korea
  2. 2.College of Pharmacy, Institute of Pharmaceutical Science and TechnologyHanyang University,AnsanSouth Korea

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